Conformational preferences and basicities of monofluorinated cyclopropyl amines in comparison to cyclopropylamine and 2-fluoroethylamine

Abstract

Fluorine substituents in organic molecules do dramatically influence the electronic structure of neighbouring functional groups and the conformation of molecules. Hence the presence of fluorine in a compound changes its chemical reactivity and biological activity. On the basis of MP2 and SCS-MP2 calculations, we discuss the conformational preferences and basicity of the diastereoisomeric 2-fluorocyclopropylamines (cis-2 and trans-2) in comparison to those of cyclopropylamine (1) and 2-fluoroethylamine (3). 1 and 2 are viewed as model compounds for the antidepressant drug tranylcypromine (trans-2-phenylcyclopropylamine, 1a) and its fluorinated derivatives 2. The potential energy profile for the rotation of the amino group in cis-2 differs from that of trans-2 and 1 which have very similar rotational curves. For 2 the global minimum conformer is trans-2a and the lowest energy cis-conformer 2c is less stable by 2.57 kcal mol(-1). The calculated enthalpy differences between the conformers gauche-1b and s-trans-1a (2.0 kcal mol(-1)) as well as between gauche-3b and gauche-4a (0.2 kcal mol(-1)) agree well with the available experimental data of 2.0 kcal mol(-1) and 0.1 +/- 0.3 kcal mol(-1), respectively. The calculated gas phase proton affinities (PA) of 1 (217.6 kcal mol(-1)), cis-2c (215.6 kcal mol(-1)), and trans-2a (209.3 kcal mol(-1)) follow the trends of the pKa values measured in solution for the diastereomeric 2-phenylcyclopropylamines 1a and 1b and their fluorinated derivatives cis-2 and trans-2. It is shown that the conformational preferences and basicity of the investigated molecules are due to stereoelectronic effects from hyperconjugative interactions which lead to different local charge distributions and different hybridization of the nitrogen lone-pair. The basicity of gauche-3a (PA = 215.3 kcal mol(-1)) and anti-3b (PA = 210.1 kcal mol(-1)) is controlled by the charge of the nitrogen atom, while that of cis-2c and trans-2a is overlap controlled as a result of different hybridization of the nitrogen lone-pair [sp4.34 (cis-2c), sp4.07 (trans-2a)].

The fluorine-NHC gauche effect: a structural and computational study

“…This value is typical of the stabilisation imparted by antiperiplanar hyperconjugative σ C-H → σ* C-F and σ C-H → σ* C-N interactions, in preference to σ C-N → σ* C-F and σ C-F → σ* C-N . Similar stereoelectronic gauche effects in NCCF systems have previously been described for imines, [44] amines, [6,[45][46][47] and amides. [6,48] Free NHCs and their precursor cations therefore follow the pattern found in other NCCF systems as far as the gauche preference is concerned.…”

“…The magnitude of this stabilisation is characteristic of an electrostatic gauche effect, which orients the partially negatively charged fluorine preferentially towards the cationic moiety, similarly to the situation seen in N-(2-fluoroethyl)iminium, [7a] -pyridinium, [45] or -ammonium [6,46,47] systems. The Hirshfeld partial charges for 23 (which are practically independent of the torsion angle) are -0.13e (F), 0.00 (both N), and +0.24e (C carb H).…”

Synthesis and Physicochemical Properties of 3‐Fluorocyclobutylamines

“…In contrast to cyclobutanes 13a – c , the fluorine effect is more pronounced for cyclopropyl compounds 18 ; thus, trans isomers, for which F and NH 3 + are in syn ‐orientation to each other, are more basic then the corresponding cis isomers, for which F and NH 3 + are in anti ‐orientation. This can be ascribed to a hyperconjugative interaction leading to weaker proton affinity of compounds with anti ‐ over syn ‐orientation of fluorine and amino functions 15a,16a. As another result, for trans ‐ 13a – c / 18a – c pairs, the Δp K a is lower (1.49–1.56) than those of the cis ‐ 13b , c / 18b , c pairs (1.85–1.90).…”

“…Having both isomers of the fluorinated cyclobutanes cis/trans-6 and cis/trans-13b,c in hand, we wanted to study the influence of fluorine on the basicity of the NH 2 group. Well-studied involvement of fluorine in weak bonds, which are considered as charge-dipole interactions [10d,15] or hydrogen bonds, [16] often lead to significant change of pK a values. [10a-10d] In the case of compounds 6 and 13, we expected to observe this kind of interaction for trans isomers, for which fluorine and NH 3 + are in cis-orientation to each other.…”

Do GluN2B subunit containing NMDA receptors tolerate a fluorine atom in the phenylalkyl side chain?

“…18,19 Moreover, a fluorine atom should influence the conformation of the alkyl side chain, as a gauche orientation of the fluorine atom and the basic amino moiety in β-position represents a preferred conformation. 20,21…”